The two main antigen receptors in the jawed vertebrate immune systems that recognize antigens specifically are the B and T cell receptors. Although both receptors are generated by the same genetic mechanisms and possess an overall similar structure, they recognize antigenic ligands in fundamentally distinct ways. BCRs recognize conformational epitopes, whereas TCRs recognize small antigenic structures, often peptides derived from antigenic proteins, bound to molecules of the Major Histocompatibility Complex (MHC). The molecular basis for this MHC restriction remains essentially unknown. The proposed studies aim at testing the hypothesis that the TCR repertoire is predisposed to recognize MHC molecules in the absence of any selective pressure. Furthermore, we propose to identify the rules, if they exist, that drive this interaction. With the recent advance of the se of chimeric T cell antigen receptors as a promising form of cancer immunotherapy, an understanding of this phenomenon is absolutely fundamental. By gaining an appreciation for why and how TCRs recognize MHC, we can harness its power to better understand and modulate immune responses to infections, tumors, or transplants.